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Abstract

Background

Although capecitabine has theoretical advantages in the pharmacokinetics, such as
higher intratumoral and lower systemic concentration, relative to bolus 5-fluorouracil
(5-FU), outcomes of chemoradiotherapy (CRT) with capecitabine or bolus 5-FU have not
been directly compared in patients with locally advanced pancreatic cancer. Therefore,
we retrospectively compared the outcomes, including toxicity, tumor response, and
overall survival, of oral capecitabine plus radiotherapy (RT) with bolus 5-FU plus
RT, in patients with locally advanced pancreatic cancer.

Methods

Between August 2006 and January 2012, 98 patients with locally advanced pancreatic
cancer received CRT, with 52 receiving concurrent oral capecitabine and 46 receiving
bolus injection of 5-FU. Primary tumor and overall response after CRT were evaluated
radiologically, and toxicity, tumor response, and overall survival (OS) were compared
in the two groups.

Conclusions

Capecitabine plus RT may be a safe and feasible regimen for patients with locally
advanced pancreatic cancer, with similar efficacy and low rates of toxicities compared
with bolus 5-FU plus RT.

Keywords:

Pancreatic cancer; Chemoradiotherapy; 5-Fluorouracil; Capecitabine

Introduction

Surgical resection is the only curative treatment for pancreatic cancer, but only
10–15% of patients have localized and resectable disease at diagnosis. Approximately
50% of pancreatic cancer patients present with distant metastatic disease and 30%
present with localized and unresectable disease. The Gastrointestinal Tumor Study
Group (GITSG) trials [1-3] showed that chemoradiotherapy (CRT) with bolus injection of 5-fluorouracil (5-FU)
yielded a modest survival benefit when compared with radiotherapy (RT) or chemotherapy
alone. Since then, CRT plus bolus 5-FU has been regarded as a standard therapy for
patients with locally advanced pancreatic cancer. Despite recent advances in diagnostics
and therapeutics, the prognosis of patients with locally advanced pancreatic cancer
has remained poor, due to high rates of local progression and distant metastasis.
Thus, various chemotherapeutic regimens, with various dosages and schedules and with
or without RT, have been tested to improve survival [4-8].

Capecitabine, an oral prodrug of 5-FU, is absorbed by the gastrointestinal tract and
metabolized to 5-FU by a cascade of three enzymes. Capecitabine is converted by carboxylesterase
in the liver to 5′-deoxy-5-fluorocytidine (5′-DFCR), by cytidine deaminase in the
liver and tumor tissue to 5′-deoxy-5-fluorouridine (5′-DFUR), and by thymidine phosphorylase
(TP) to 5-FU in tumor tissue. TP is more concentrated in tumor tissue than in normal
tissue, and is upregulated by radiation in tumor tissue but not in normal tissue.
Thus, oral capecitabine can result in a higher intratumoral and lower systemic 5-FU
concentration than bolus 5-FU [9,10]. This improved therapeutic index, along with more favorable pharmacokinetics (similar
to those of protracted infusion of 5-FU), and convenient oral administration without
the need for central venous access and an ambulatory infusion pump, make capecitabine
particularly appealing to use in conjunction with RT. To our knowledge, however, outcomes
of CRT with capecitabine or bolus 5-FU have not been directly compared in patients
with locally advanced pancreatic cancer. We therefore retrospectively compared the
outcomes, including toxicity, tumor response, and overall survival, of oral capecitabine
plus RT with bolus 5-FU plus RT, in patients with locally advanced pancreatic cancer.

During the same study period, 46 patients who refused to participate in this protocol
received CRT plus 5-FU, the routine clinical practice regimen in our institution for
patients with locally advanced pancreatic cancer. This study was conducted in accordance
with the guidelines of the institutional review boards of the National Cancer Center.

Before CRT, patients were given physical examinations and underwent blood tests, including
complete blood count, liver function tests, and serum CA 19–9 concentrations; chest
radiography, and dynamic CT and/or PET of the abdomen and pelvis. All tumors were
staged using the American Joint Committee on Cancer (AJCC), 6th edition, and were classified as stage cT4 (unresectable disease), based on the CT
scans, with tumor extension to the celiac axis or superior mesenteric artery or occlusion
of the superior mesenteric-portal venous confluence. Primary tumors were measured
bi-dimensionally, with lymph node involvement defined by the presence of a lymph node
≥1 cm in the short-axis, with a spiculated or indistinct border, or with a mottled
heterogeneous pattern on CT with or without PET (n = 87) [11]. Table 1 shows the baseline patient characteristics.

Treatment

Radiotherapy

Prior to RT, all patients underwent CT simulation, with their targets defined in accordance
with the International Commission on Radiation Units and Measurements Report 50. The
gross tumor volume (GTV) encompassed the gross tumor, as defined by contrast CT or
PET scan. The clinical target volume (CTV) included the GTV and the volumes of regional
lymph nodes, including the porta hepatic, pericholedochal, celiac, and pancreaticoduodenal
nodes. The initial and boot planning target volume (PTV) included the CTV and GTV
plus a 5–10 mm margin. All patients underwent three-dimensional treatment planning,
such that the PTV would be encompassed by a 90% isodose volume of the prescribed dose.

An initial dose of 45 Gy in 25 fractions was delivered to the primary tumor and regional
lymph nodes, followed by a boost of 10.8 Gy in 6 fractions to the gross tumor, 5 days
a week. All patients received a total radiation dose of 55.8 Gy in 31 fractions.

Chemotherapy

Capecitabine or 5-FU was delivered concurrently with RT. The capecitabine group received
an oral dose of 800 mg/m2 twice daily for the duration of RT with weekend breaks. The 5-FU group received two
cycles of intravenous bolus injection of 5-FU (400 mg/m2/d) for 3 days in the first and fifth weeks of RT.

Treatment after CRT and evaluation

Following completion of CRT, patients were evaluated clinically and underwent CT scans
of the abdomen, chest radiography, and serum CA 19–9 measurements to determine tumor
response and resectability. Patients who had resectable disease after CRT was considered
for surgical resection, whereas patients who still had unresectable disease were considered
for gemcitabine based chemotherapy (1000 mg/m2over 30 minutes intravenously once weekly for 3 of every 4 weeks). Patients who refused
further chemotherapy or had poor performance status received supportive care.

Serum samples for measurement of CA 19–9 were obtained from all patients within 2 weeks
of the initiation of CRT (pre-treatment level) and 1 month after CRT (post-treatment
level). The percent decrease in CA 19–9 concentration was calculated as: CA 19–9 percent
decrease (%) = [(pre-treatment CA 19–9 – post-treatment CA 19–9)/pre-treatment CA
19–9] × 100. Tumor responses were determined by comparison of CT scans taken before
and 1 month after CRT using the Response Evaluation Criteria in Solid Tumors guidelines
[12]. A complete response (CR) was defined as the disappearance of the primary tumor.
A partial response (PR) was defined as ≥30% reduction in the longest diameter of the
primary tumor. Progressive disease (PD) was defined as a ≥20% increase in the longest
diameter of the primary tumor or the appearance of one or more new lesions. Stable
disease (SD) was defined as a response that did not qualify as a PR or a PD. Objective
response rates were calculated as the rate of CR + PR. Patients with CR or PR were
considered “Responders”, and those with SD or PD were considered “Non-responders”.
Toxicity was recorded according to the National Cancer Institute Common Terminology
Criteria for Adverse Events, version 3.0. Due to difficulties in accurately scoring
lower grades of acute toxicity in patients with pancreatic cancer, only grade 3 or
higher acute toxicities are compared.

Follow-up and statistical analysis

After completion of treatment, patients were given follow-up examinations every 2–4 weeks
for the first 3 months, and then every 3 months. For most patients, follow-up evaluations
at each visit included a physical examination, complete blood count, liver function
test, serum CA 19–9 measurement, chest radiography, and dynamic CT scan of the abdomen
and pelvis. Recurrence was proven by biopsy or cytology, and/or by radiological findings
that indicated an increase in tumor size.

A pretreatment serum CA 19–9 of 400 U/mL, the significant cutoff point in our previous
reports [13,14], or a 40% decrease in CA 19–9, close to the median value for each group, was chosen
as a cutoff point for comparison of patient survival rates. Parameters in the capecitabine
and 5-FU groups were compared using chi-square tests, Fisher’s exact tests, and t-tests,
as applicable. Overall survival (OS) was defined as the interval from the commencement
of CRT to the date of death or last follow-up and its probability was calculated by
the Kaplan–Meier method. Univariate and multivariate analyses were performed using
the log rank test and Cox’s proportional hazard model, respectively, to evaluate prognostic
factors associated with OS. All statistical tests were two-sided and were performed
using STATA software (ver. 9.0; Stata Corp., College Station, TX). P values less than 0.05 were considered statistically significant.

Results

Patient characteristics

The clinical parameters of the capecitabine and 5-FU groups were similar (Table 2). The median follow-up time for all patients was 12.3 months (range, 2.3–65.8 months)
and was similar in the capecitabine and 5-FU groups [12.6 months (range, 2.3–39.2 months)
vs. 11.2 months (range, 4.6–65.8 months), p =0.837].

Table 2.Comparison of toxicities* between the capecitabine and 5-fluorouracil (5-FU) groups

Toxicity

Treatment was well tolerated in both groups and there were no treatment-related deaths.
The details of the distribution of toxicities between the capecitabine and 5-FU groups
are summarized in Table 2. None of the patients in the capecitabine group developed Grade ≥3 toxicities, whereas
4 patients each (8.7%) in the 5-FU group developed Grade ≥3 hematologic and non-hematologic
toxicities (p = 0.045 each).

Tumor response and overall survival

Overall and primary tumor responses were evaluated one month after CRT by imaging
modalities, except in one patient who had no available radiologic images after CRT.
No patient in either group achieved a CR in primary tumor or overall response. Primary
tumor response was as follows: PR in 29 patients (29.9%), SD in 67 (69.1%), and PD
in 1(1.0%). Overall tumor response was as follows: PR in 14 patients (14.4%), SD in
25 (25.8%), and PD in 58 (59.8%). Of the 58 patients with overall tumor responses
of PD, 57 (83.6%) had distant metastases, regardless of primary tumor response (i.e.,
15 had primary tumor responses of PR and 42 of SD); one patient (1%) showed primary
tumor progression without distant metastasis. Overall and primary tumor responses
and percent decreases in CA 19–9 concentrations in the capecitabine and 5-FU groups
are summarized in Table 3. None of these between group differences was statistically significant (p > 0.05 each). Of the 98 patients, 7 (7.1%) underwent surgical resection, with 5 being
margin negative and 2 margin positive. Rates of conversion to resectability were similar
in the capecitabine and 5-FU groups [4/52 (7.7%) vs. 3/46 (6.5%), p = 1.000]. Of the 7 resected patients, 2 developed locoregional recurrence, 3.5 and
5.5 months later, with the remaining 5 continuing to be locoregionally controlled.
After completion of CRT, 47 patients (48%), received gemcitabine based chemotherapy
until disease progression, treatment-limiting toxicity, or death; the median number
of chemotherapy cycles was 3 (range, 1–17). The remaining 51 patients (52%) did not
receive maintenance chemotherapy because of patient refusal or poor performance status.
The distribution of patients receiving maintenance chemotherapy were similar in the
capecitabine and 5-FU groups [26/52 (50%) vs. 21/46 (45.7%), p = 0.667].

Table 3.Tumor responses* in the capecitabine and 5-fluorouracil (5-FU) groups

Discussion

We found that the rates of Grade ≥3 hematologic (0% vs. 8.7%, p = 0.045) and non-hematologic (0% vs. 8.7%, p = 0.045) toxicities were significantly lower in the capecitabine group than in the
5-FU group. Lower toxicity rates may have been due to the pharmacodynamic advantages
of oral capecitabine relative to bolus 5-FU [15]. Capecitabine is a tumor-selective fluoropyrimidine carbamate that is converted to
active 5-FU by TP, an enzyme of higher abundance in tumor than in normal tissue that
is upregulated by radiation in tumor but not in normal tissue [9,10]. Thus, theoretically, capecitabine could show lower rates of toxicity than bolus
5-FU. A previous study found that the rate of Grade ≥3 hematologic toxicity was lower
in patients receiving capecitabine than 5-FU during preoperative CRT for locally advanced
rectal cancer (1.5% vs. 7.8%, p = 0.04), similar to our results, but that rates of Grade ≥3 diarrhea (8.6% vs. 2.1%,
p = 0.006) and hand-foot syndrome (2%vs. 0%, p = 0.061) were higher in the capecitabine group [16]. However, a phase II trial of induction chemotherapy with gemcitabine and cisplatin
followed by CRT with capecitabine in patients with locally advanced pancreatic cancer
showed that the rates of Grade ≥3 diarrhea (5.4%) and hand-foot syndrome (0%) were
low during CRT [17], similar to our findings. These findings implied that the lower rates of Grade ≥3
non-hematologic toxicity in the capecitabine than in the 5-FU group in our study maybe
due to genetic differences in tolerability or susceptibility to capecitabine between
Caucasians and Asians, as the conversion rate of tegafur to fluorouracil is different
between Caucasians and Asians due to polymorphic differences in the CYP2A6 gene [18,19]. However, due to the relatively small number of patients in the capecitabine group
(n = 52), which may be insufficient to determine the overall actual toxicity rates
thoroughly and low incidence of toxicities in western study treated with CRT with
capecitabine [20], more comprehensive and larger-scale studies should be needed.

Protracted infusion of 5-FU and capecitabine, which prolongs the exposure of non-cycling
tumor cells to 5-FU, may enhance cytotoxicity relative to bolus 5-FU. Protracted infusion
of 5-FU or capecitabine during adjuvant CRT has been shown to improve relapse-free
survival (RFS) and OS, compared with bolus 5-FU, in patients with rectal cancer [16,21]. In contrast, the Intergroup 0144 study, which compared different 5-FU based chemotherapeutic
regimens in rectal cancer, found that protracted and bolus infusion of 5-FU yielded
similar RFS and OS, and our previous report [22] showed that capecitabine and bolus 5-FU resulted in similar radiologic and pathologic
tumor responses in patients receiving preoperative CRT for rectal cancer. However,
to date, it has been remained unclear whether chemotherapeutic regimens, among a protracted
infusion of 5-FU, capecitabine, or bolus injection of 5-FU, can result in superior
outcomes in patients with pancreatic cancer. We found that capecitabine, which mimics
the protracted infusion of 5-FU, and bolus 5-FU yielded similar tumor responses and
overall survival in patients with locally advanced pancreatic cancer.

A randomized trial found that, compared to5-FU, gemcitabine yielded better outcomes,
including alleviation of disease-related symptoms and longer OS, in patients with
advanced, symptomatic pancreatic cancer [23], and thus various dosages and schedules of gemcitabine based chemotherapy, with or
without RT, have been tried to improve survival in locally advanced pancreatic cancer
patients [4-6,8]. These studies, however, showed that gemcitabine based chemotherapy, with or without
oxaliplatin, paclitaxel, docetaxel, and tyrosine kinase inhibitors, resulted in high
rates of severe toxicities, without survival benefits, compared to 5-FU. Thus, 5-FU
continues to be used as a concurrent chemotherapeutic agent during CRT [5]. To evaluate the effectiveness and safety of capecitabine, we compared outcomes,
including toxicity, tumor response and overall survival, of RT plus capecitabine or
bolus 5-FU, in patients with locally advanced pancreatic cancer.

This study was retrospective and thus had certain inherent limitations. First, it
included relatively small numbers of patients in the capecitabine (n = 52) and 5-FU
(n = 46) groups, which may have been insufficient to compare outcomes thoroughly.
Second, this was a retrospective comparison study of two groups with different chemotherapeutic
regimens, not a randomized trial. Thus, further larger scaled and comprehensive studies
are required to accurately compare the outcomes of these two chemotherapy regimens
in patients with locally advanced pancreatic cancer. However, in present study, the
characteristics of patients in the two groups did not differ significantly, and each
chemotherapeutic regimen was decided according to patient’s preferences.

Conclusion

In conclusion, we compared the outcomes of CRT with capecitabine or bolus 5-FU in
patients with locally advanced pancreatic cancer. We found that CRT with capecitabine
had low toxicity rates, but yielded similar tumor responses and overall survival compared
with CRT with bolus 5-FU. These findings suggest that capecitabine may be a safe and
feasible chemotherapy regimen in patients with locally advanced pancreatic cancer
treated with CRT.

Competing interests

None of the authors have potential conflicts of interest.

Authors’ contributions

THK, SMW, WJL and YJK are responsible for the study design. THK, WJL, SMW, YJK, TSK,
SSH, BHK, SHM, SSK, YHK, SJP, DYK and JWP collected the clinical data and drafted
the manuscript. THK, SMW, WJL, JK, DYK and YJK revised the manuscript. YJK, WJL and
SMY collected the pathologic data and analysis THK, DYK, WJL and SMW were responsible
for the treatment and evaluation of the patients. SJP, SHM, SSK, DYK, JWP and THK
provided oversight of the analysis of data and reviewing of the manuscript. All authors
read and approved the final manuscript.

Acknowledgments

This work was supported by a National Cancer Center Grant (NCC-1310080, 1241110 and
1340940).

References

A multi-institutional comparative trial of radiation therapy alone and in combination
with 5-fluorouracil for locally unresectable pancreatic carcinoma. The Gastrointestinal
Tumor Study Group